Phototherapy compositions and methods

ABSTRACT

Compositions containing a photoactivable agent and an agent that absorbs or blocks extraneous radiation during phototherapy are useful and used in methods to treat leukocyte mediated autoimmune diseases such as psoriasis, CTCL, and vertiligo.

BACKGROUND OF THE INVENTION

This invention relates to topical compositions of photoactivable agentsand agents for absorbing or blocking extraneous radiation duringphototherapy. The compositions are useful in methods for the treatmentof various disorders such as psoriasis, CTCL, vertiligo, and otherleukocyte mediated diseases.

A number of human diseases are mediated by certain types of leukocytessuch as lymphocytes. Excessive or abnormal lymphocyte populations canresult in numerous adverse effects to patients including the functionalimpairment of bodily organs, leukocyte mediated autoimmune diseases andleukemia related disorders. Some of these abnormal leukocyte mediatedconditions can be alleviated effective using phototherapy in conjunctionwith psoralens. (See New England Journal of Medicine. 316:297 (1987);and Scientific American, August 1988, p. 68). The combination ofpsoralen ingestion or application together with UVA light to the skin isreferred to as PUVA therapy. The psoralen is acts as a photosensitizerfor the UVA treatment of the effected skin.

PUVA treatments involving the oral administration of 8-MOP followed byexposure to ultraviolet-A ( UVA light 320-400 nm wavelength) is oftenefficacious in the management of debilitating psoriasis vulgaris, ahyperproliferative disease of the epidermis. It has also beendemonstrated that plaque stage cutaneous T cell lymphoma (CTCL), whenlimited to the skin, can respond favorably to this treatment (GilchrestB. A., et al. Cancer (1976) 38: 683-689; Honigsmann H., et al. J. Am.Acad. Derm. (1984) 10:238-245).

There are several disadvantages with oral PUVA. In oral PUVA therapy,patients can experience nausea or find it difficult to achievetherapeutic levels of the psoralen. Additionally patients who can betreated with current oral dosages of methoxsalen may suffer fromphototoxicity if they do not avoid sunlight or artificial sources of UVAlight for 24 hours after receiving therapy. Other disadvantages includeexposure of the affected skin area and the area surrounding the affectedarea with incidental UVB and or UVA radiation.

To avoid the systemic side effects of oral PUVA, topical PUVA treatmentshave been used in some cases. Psoralens such as 8 MOP tend to rapidlydiffuse into and out of the skin making application to skin andtreatment time thereafter difficult to manage. One approach to such PUVAtreatment is the so-called “Bath PUVA” treatment in which the psoralenis essentially washed onto the patient in widespread fashion followed bybroad UVA exposure. Bath PUVA has been used to treat dermatoses such asin lichen planus, systemic sclerosis and generalized morphoea, urticariapigmentosa, mycosis fungoides, polymorphic light eruption, prurigosimplex subacuta, nodular prurigo, aquagenic pruritus, and lymphomatoidpapulosis. See See Rhodes L. E. Guidelines for topical PUVA: a report ofa workshop of the British Photodermatology Group, British Journal ofDermatology, 2000: 142: 22-31.

Other more locally applied topical psoralen formulations such asointment, paint, aqueous gel, emulsion, lotion, and/or cream have alsobeen used to treat dermatoses. These dermatoes include atopicdermatitis, lichen planus, systemic slerosis and generalized morphoea,vitiligo, uraemic pruitus, hyperkeratotic eczema, dyshidrotic eczema,hyperkeratotic psoriasis, and palmoplantar pustulosis. See Rhodes L. E.Guidelines for topical PUVA: a report of a workshop of the BritishPhotodermatology Group, British Journal of Dermatology, 2000: 142:22-31.

While topical PUVA treatments avoid the gastrointestinal and othersystemic side-effects, topical PUVA treatments, as with oral and bathPUVA treatments, still suffer from the incidental exposure to UVradiation in the affected skin area and the surrounding skin area. For aPUVA treatment, commercially available high output UVA (320-400 nm)tube-style are utilized. However, these UVA radiation sources also emitsome radiation in the 290-320 nm UVB region. Thus patients undergoingPUVA treatment are also exposed inadvertently to UVB radiation. Sideeffects include erythema, blistering and hyperpigmentation of thesurrounding skin.

Psoralen formulations and method of treatments which allow a patient toundergo efficacioius PUVA treatments while minimizing exposure toincidental radiation in the affected area as well as in the areasurrounding the affected area would be welcomed.

Current 8-MOP formulations, such as paints or ointments do not protectpatients from UVB exposure and do not provide a means for protecting thearea surrounding the affected area.

Despite the developments in psoralen compositions and methods of usingthem there remains a need for a psoralen formulation that is effectivefor phototherapy with UVA while protecting the affected area fromresidual UVB emitted by the irradiation source. The psoralen-basedformulations provided in this specification comprise a UVB absorbingagent for providing such protection to the affected areas of the skin.The methods of the instant invention also alleviate undesirableincidental UVB and UVA radiation by administering to the areasurrounding the affected area with a composition containing UVB and/orUVA absorbing agents.

The compositions of this invention comprise an oil phase havingnon-volatile compounds, photoactivable compounds such as a psoralen, andan UVB absorber. The oleaginous compositions of this invention contain apsoralen and an UVB absorbing agent in an essentially non-aqueousformulation.

The present invention also includes an improved PUVA method fortreatment of diseases such as atopic dermatitis, lichen planus, systemicslerosis and generalized morphoea, vitiligo, uraemic pruitus,hyperkeratotic eczema, dyshidrotic eczema, hyperkeratotic psoriasis, andpalmoplantar pustulosis. The affected skin areas are treated with UVAlight and a pharmaceutically acceptable composition containing apsoralen and block out inadvertent UV radiation in the area surroundingthe affected area with UVA and UVB absorbing agents.

SUMMARY OF THE INVENTION

In one aspect of the invention a composition useful for PUVA therapycomprises a photoactivable substance and an agent that blocks or absorbsextraneous radiation. It can be in the form of an oil-in-water emulsioneffective to alleviate at least one symptom of psoriasis, vitiligo,cutaneous T-cell lymphoma, sleroma, chronic lymphocytic leukemia, atopicdermatitis, or adult T-cell leukemia. The agent that blocks or absorbsextraneous radiation can be a UVB absorber.

In another aspect of the invention, the composition is in the form of anoil, ointment, cream, lotion, gel, or paste effective to alleviate atleast one symptom of psoriasis, vitiligo, cutaneous T-cell lymphoma,sleroma, chronic lymphocytic leukemia, atopic dermatitis, or adultT-cell leukemia, in which the photoactivable compound is a psoralenselected from 5-methoxypsoralen; 8-methoxy-psoralen;4,5′8-trimethylpsoralen; 4-methylpsoralen; 4,4-dimethylpsoralen;4-5′-dimethyl-psoralen; 4′-aminomethyl-4,5′,8-trimethyl-psoralen;4′-hydroxymethyl-4,5′,8-trimethylpsoralen; and 4′,8-methoxy psoralen;and the UVB absorbing agent is selected from3-(4-methylbenzylidene)camphor; 3-benzylidenecamphor; 2-ethyl-hexyl4-(dimethylamino)benzoate; amyl 4-(dimethylamino)-benzoate, ethyl4-(dimethylamino)benzoate, n-butyl 4-(dimethylamino)benzoate, i-propyl4-(dimethylamino)-benzoate, i-amyl 4-(dimethylamino)benzoate, n-amyl4-(dimethylamino)benzoate, cyclohexyl 4-(dimethylamino)-benzoate,n-octoyl 4-(dimethylamino)benzoate; 2-ethyl-hexyl 4-methoxycinnamate;isopentyl 4-methoxycinnamate; i-propyl 4-methoxycinnamate, i-amyl4-methoxycinnamate, cyclohexyl 4-methoxycinnamate; 2-ethylhexylsalicylate, 4-isopropylbenzyl salicylate; 3,3,5-trimethyl-cyclohexylsalicylate; 2-hydroxy-4-methoxybenzophenone;2-hydroxy-4-methoxy-4′-methyl-benzo-phenone;2,2′-dihydroxy-4-methoxy-benzophenone; and di(2-ethylhexyl)4-methoxybenzalmalonate.

The composition can have a photoactivable compound concentration ofabout 0.01-10% by weight of said composition.

The composition can have a concentration of agent that blocks or absorbsextraneous radiation (preferably, UVB absorbing agent) about 0.05-2% byweight of said composition.

In yet another aspect of the invention, a method to alleviate at leastone symptom of psoriasis, vitiligo, cutaneous T-cell lymphoma, sleroma,chronic lymphocytic leukemia, atopic dermatitis, or adult T-cellleukemia comprises the steps of a) contacting a composition containing aphotoactivable compound and an agent that blocks or absorbs extraneousradiation to an affected area, b) contacting an area surrounding theaffected area with agent that blocks or absorbs extraneous radiation(preferably, a UVB and/or UVA absorbing agent); and c) irradiating theaffected area with UVA.

In yet a further aspect of the invention, a PUVA method involves the useof a photoactivable compound that is a psoralen selected from5-methoxypsoralen; 8-methoxypsoralen; 4,5′,8-trimethylpsoralen;4-methylpsoralen; 4,4-dimethylpsoralen; 4-5′-dimethyl-psoralen;4′-aminomethyl-4,5′,8-trimethylpsoralen;4′-hydroxymethyl-4,5′,8-trimethylpsoralen; and 4′,8-methoxy psoralen orcombinations thereof; and the UVB absorbing agent is selected from3-(4-methylbenzylidene)camphor; 3-benzylidenecamphor; 2-ethyl-hexyl4-(dimethylamino)benzoate; amyl 4-(dimethylamino)-benzoate, ethyl4-(dimethylamino)benzoate, n-butyl 4-(dimethylamino)benzoate, i-propyl4-(dimethylamino)-benzoate, i-amyl 4-(dimethylamino)benzoate, n-amyl4-(dimethylamino)benzoate, cyclohexyl 4-(dimethylamino)-benzoate,n-octoyl 4-(dimethylamino)benzoate; 2-ethyl-hexyl 4-methoxycinnamate;isopentyl 4-methoxycinnamate; i-propyl 4-methoxycinnamate, i-amyl4-methoxycinnamate, cyclohexyl 4-methoxycinnamate; 2-ethylhexylsalicylate, 4-isopropylbenzyl salicylate; 3,3,5-trimethyl-cyclohexylsalicylate; 2-hydroxy-4-methoxybenzophenone;2-hydroxy-4-methoxy-4′-methyl-benzo-phenone;2,2′-dihydroxy-4-methoxy-benzophenone; and di(2-ethylhexyl)4-methoxybenzalmalonate or combinations thereof.

In another aspect of the invention, a method to alleviate at least onesymptom of psoriasis, vitiligo, cutaneous T-cell lymphoma, sleroma,chronic lymphocytic leukemia, atopic dermatitis, or adult T-cellleukemia comprises the steps of a) contacting a therapeutic compositionhaving 8-MOP and octyl methoxycinnamate, b) contacting a compositionhaving octyl methoxycinnate to an area surrounding the affected area,and c) irradiating the area with UVA.

DETAILED DESCRIPTION

The formulations of the invention are most conveniently prepared in aform such as a gel, lotion, or ointment. The formulations contain anagent that prevents the absorption (by the patient's skin) of unwantedenergy or radiation during the course of therapy. The agent can eitherblock or absorb the unwanted or extraneous radiation. Preferably, thisagent is an energy absorbing agent and most preferably it is a UVBabsorbing agent. The formulation also contains an adequate amount of aphotoactivable compound, preferably a psoralen, that can be appliedtopically to a patient's skin lesions and, when allowed to adsorb intothe skin for a specified period of time, and exposed with appropriateradiation, provides an effective treatment for the disorders that can beeffected by PUVA treatment. Radiation can be applied in a standard UVAPUVA light box or with a more tailored application of such radiation.After the appropriate dose of light is applied the patient would removethe topical formulation by showering, washing the affected area, orusing a wipe or removal solvent.

Application of the formulation topically resolves the poorbioavailability issue and eliminates the nausea experienced by patientsutilizing the oral formulation. Likewise, photoxicity can be greatlyreduced. Furthermore, the topical formulation of the present inventionabsorbs radiation that is not of therapeutic value according to thetreatment. This extraneous radiation is ordinarily in the UVB range.

Photoactivatable compounds for use in accordance with the presentinvention preferably include compounds known as psoralens (orfurocoumarins) as well as psoralen derivatives such as those describedin, for example, U.S. Pat. Nos. 4,321,919 and 5,399,719. Thephotoactivable compounds that can be used in accordance with the presentinvention include psoralen and psoralen derivatives; 8-methoxypsoralen;4,5′8-trimethylpsoralen; 5-methoxypsoralen; 4-methylpsoralen;4,4-dimethylpsoralen; 4-5′-dimethylpsoralen;4′-aminomethyl-4,5′,8-trimethylpsoralen;4′-hydroxymethyl-4,5′,8-trimethylpsoralen; 4′,8-methoxypsoralen; and a4′-(omega-amino-2-oxa) alkyl-4,5′,8-trimethylpsoralen, including but notlimited to 4′-(4-amino-2-oxa)butyl-4,5′,8-trimethylpsoralen. In oneembodiment, the photosensitive compound comprises the psoralenderivative amatosalen S-59,(2)3-[(2-Aminoethoxy)-methyl]-2,5,9-trimethyl-7H-furo[3,2-g][1]benzo-pyran-7-onehydrochloride(Cerus, Corp., Concord, Calif.). See, e.g., U.S. Pat. Nos. 6,552,286;6,469,052; and 6,420,570 each of which is incorporated in its entiretyby reference. In the most preferred embodiment, the photosensitivecompound is 8-methoxypsoralen(9-methoxy-7H-furo[3,2-g][1]-benzopyran-7-one or 8-MOP). 8-Methoxysalenis a naturally occurring photoactive substance found in the seed of theAmmi majus (umbelliferae plant). See, for example, Fahmy et al., “AmmiMajus Linn. Pharmacognostical Study and Isolation of CrystallineConstituent, Ammoidia”, Quant. J. Pharm. and Pharmacol., 20:281, (1948).It has the following structure:

The agent that prevents the absorption of unwanted radiation by thepatients is most preferably an energy absorbing agent. That is, thesubstance absorbs the radiation having the unwanted wavelengths so thatit is not absorbed by the patient's skin. These substances are mostpreferably UVB absorbing agents and can be any compound or combinationof compounds capable of absorbing ultraviolet light in the range of 290to 320 nanometers and which are safe for use on human skin. A widevariety of UVB absorbing agents are suitable for such use. They includesalts or acid neutralized forms of acidic UVB absorbing agents. Examplesof such ultraviolet light-absorbing compounds include3-benzylidenecamphor derivatives; 4-aminobenzoic acid derivatives;esters of cinnamic acid; esters of salicylic acid; derivatives ofbenzophenone; and esters of benzalmalonic acid. Preferred UVB absorbingagents are selected from 2-ethylhexyl-2-cyano-3,3-diphenylacrylate(referred to as octocrylene), 2-phenyl-benzimidazole-5-sulphonic acid(PBSA), cinnamates derivatives such as 2-ethylhexyl-p-methoxycinnamateand octyl-p-methoxycinnamate, TEA salicylate, octyldimethyl PABA, andmixtures thereof. Even more preferred UVB absorbing agents include3-(4-methylbenzylidene)camphor and 3-benzylidenecamphor; 2-ethyl-hexyl4-(dimethylamino)benzoate amyl 4-(dimethylamino)benzoate, ethyl4-(dimethylamino)benzoate, n-butyl 4-(dimethylamino)benzoate, i-propyl4-(dimethylamino)benzoate, i-amyl 4-(dimethylamino)benzoate, n-amyl4-(dimethylamino)benzoate, cyclohexyl 4-(dimethylamino)benzoate,n-octoyl 4-(dimethylamino)benzoate; 2-ethylhexyl 4-methoxycinnamate andisopentyl 4-methoxycinnamate; i-propyl 4-methoxycinnamate, i-amyl4-methoxycinnamate, cyclohexyl 4-methoxycinnamate; 2-ethylhexylsalicylate, 4-isopropylbenzyl salicylate and homomenthyl salicylate;2-hydroxy-4-methoxybenzophenone,2-hydroxy-4-methoxy-4′-methylbenzo-phenone and2,2′-dihydroxy-4-methoxybenzophenone; and di(2-ethylhexyl)4-methoxybenzalmalonate; 2-ethylhexyl-2-cyano-3,3-diphenylacrylate(referred to as octocrylene).

The compositions preferably comprise an amount of absorbing or blockingagent that is safe and effective to provide UVB protection eitherindependently, or in combination with, other UV absorbing agent presentin the compositions. The compositions preferably comprise from about0.1% to abut 16%, more preferably from about 0.1% to about 12%, and mostpreferably from about 0.5% to about 8% by weight, of absorbing orblocking agent.

The preferred compositions contain at least one UVB absorbing compoundaccording to the present invention and at least one psoralen compoundaccording to the present invention as well as other components used topresent the combination as a topical formulation. Preferably, theseother components include an oil phase component, an aqueous phasecomponent, and/or a surfactant component for emulsifying, dispersing orsolubilizing the component materials.

The compositions of this invention can also be formulated and packagedas sterile ointments and lotions in containers suitable foradministering a unit dose of the composition to a subject receiving thePUVA treatment. Containers suitable for administering unit doses offormulation include syringes, ampoules, vials, tubes (e.g., those whichrelease products when squeezed or which otherwise extrude products). Theappropriate amount of the psoralen composition is added to syringe,ampoule, vial, or tube which is then stoppered or sealed and sterilized.When stoppered, a teflonized stopper is preferred.

For topical applications, lotions, ointments, or emulsions (preferably,oil-in-water emulsions) may be prepared and employed. These may beformulated with any one of a number of pharmaceutically acceptablecarriers known in the art. A pharmaceutically acceptable carrier doesnot cause an allergic reaction or other untoward effect in patients towhom it is administered. Typical pharmaceutically acceptable carriersinclude, for example, one or more of water, saline, phosphate bufferedsaline, dextrose, glycerol, ethanol. Pharmaceutically acceptablecarriers may further comprise auxiliary substances such as wetting oremulsifying agents, preservatives or buffers, which enhance the shelflife or effectiveness of the topical composition.

Preferred oil-in-water emulsions are prepared in two phases, an oilphase and an aqueous phase. In the acqueous phase, water (preferablydeionized) preferably comprises at least 50 wt. % of the composition,e.g., about 50-75 wt. %.

The aqueous phase can further comprise humectant. Humectants are agentswhich promote the retention of moisture, e.g. moisturizers. Examples ofhumectants are polyhydric alcohols including polyalkylene glycols andmore preferably alkylene polyols and their derivatives. Illustrative arepropylene glycol, dipropylene glycol, polypropylene glycol, polyethyleneglycol, sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-butyleneglycol, 1,2,6-hexanetriol, ethoxylated glycerin, propoxylated glycerinand mixtures thereof. Preferably the humectant is sorbitol. Whenpresent, amounts of humectant may range anywhere from 1 to 50%,preferably from 1 to 10%, optimally from 2 to 5% by weight.

The aqueous phase can further comprise preservatives. Preservatives areused to protect the composition form degradation. Suitable preservativesare alkyl esters of para-hydroxybenzoic acid. Other preservatives thathave more recently come into use include hydantoin derivatives such as1,3-bis(hydroxymethyl)-5,5-dimthylhydantoin, propionate salts, and avariety of quaternary ammonium compounds such as benzalkonium chloride,quaternium 15 (Dowicil 200), benzethonium Chloride, andmethylbenzethonium chloride. Particularly preferred preservatives aredisodium EDTA, phenoxyethanol, methyl paraben, propyl paraben,imidazolidinyl urea (commercially available as Germall 1157), sodiumdehydroacetate and benzyl alcohol. The preservatives should be selectedhaving regard for the use of the composition and possibleincompatibilities between the preservatives and other ingredients in theoil-in-water emulsion. Preservatives preferably are employed in amountsranging from about 0% to about 5%, more preferably from about 0.01% toabout 2.5%, and most preferably from about 0.01% to about 1%, by weightof the composition.

The aqueous phase may further comprise a water-soluble antioxidant.Antioxidants are used to protect ingredients of the composition fromoxidizing agents that are included within or come in contact with thecomposition. The water-soluble antioxidants which are useful in thecompositions of this invention include ascorbic acid, sodiummetabisulfite, sodium bisulfite, sodium thiosulfite, sodium formaldehydesulfoxylate, isoascorbic acid, thioglyerol, thiosorbitol, thiourea,thioglycolic acid, cysteine hydrochloride,1,4-diazobicyclo-(2,2,2)-octane, malic acid, fumaric acid, licopene andmixtures thereof as well as any other known water-soluble antioxidantcompatible with the other components of the compositions.

Additionally, the aqueous phase can further comprise hydrophilic gellingagents or thickeners such as the acrylic acid/ethyl acrylate copolymersand the carboxyvinyl polymers sold by the B.F. Goodrich Company underthe trademark of Carbopol Registered TM resins. These resins consistessentially of a colloidally water-soluble polyalkenyl polyethercrosslinked polymer of acrylic acid crosslinked with from 0.75% to 2.00%of a crosslinking agent such as polyallyl sucrose or polyallylpentaerythritol. Examples of thickeners include Carbopol 934, Carbopol940, Carbopol 950, Carbopol 980, Carbopol 951 and Carbopol 981. Carbopol934 is a water-soluble polymer of acrylic acid crosslinked with about 1%of a polyallyl ether of sucrose having an average of about 5.8 allylgroups for each sucrose molecule. Thickeners such as Carbopol 934 or 940preferably are employed in amounts ranging from 0.1% to 0.5% by weightof the composition. A higher percentage of thickeners Carbopol 934 or940 is not desirable as psoralen 8-MOP may not be stable in a Carbopolgel. Martens-Lobenhoffer J, Rinke M, Lösche D, Gollnick H; Long-TermStability of 8-Methoxypsoralen in Ointments for Topical PUVA Therapy(‘Cream-PUVA’). Skin Pharmacol Appl Skin Physiol 1999;12:266-270.

When the compositions of the invention are prepared as oil-in-wateremulsions, the oil phase of the instant invention preferably contains atleast one emollient oil, at least one substantive oil or wax, and atleast one UVB absorbing agent. Emollient oil is an agent that softensand smoothes the skin. Emollient oil can also function as a carrier inthe absorbing into the skin the photoactive agent and agent that blocksor absorbs extraneous radiation. A substantive oil also acts as acarrier. Amounts of substantive and emollient oils preferably range fromabout 5% to 50%, more preferably from about 20% to about 40%, and mostpreferably from about 30% to 40% by weight (based on total weight of thecomposition). Variations within this range may depend on the specificcharacteristics of the whole panoply of components including, forexample, UVB absorbing agent, humectant, emulsifer, and gelling agent.Substantive oils and emollient oils are preferably selected fromnon-volatile organic oils.

Suitable substantive oil and emollient oil are preferably selected fromfatty alcohols; fatty acids; esters of mono and dibasic carboxylic acidswith mono and polyhydric alcohols; polyoxyethylenes; polyoxypropylenes;mixtures of polyoxyethylene and polyoxypropylene ethers of fattyalcohols; and mixtures thereof. Non-volatile solvents that can be usefulin the present invention may either saturated or unsaturated, have analiphatic character and be straight or branched chained or containalicyclic or aromatic rings. More preferably, the relatively polar,non-volatile liquid solvent are selected from the group consisting offatty alcohols having from about 10-30 carbon atoms; fatty acids havingfrom about 10-30 carbon atoms, for example pelargonic, lauric, myristic,palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic,ricinoleic, arachidic, behenic and erucic acids and alcohols ; esters ofmonobasic carboxylic acids and alcohols having from about 10-30 carbonatoms; esters of dibasic carboxylic acids and alcohols having from about10-30 carbon atoms; esters of polyhydric alcohols and carboxylic acidshaving from about 5-26 carbon atoms; ethoxylated, propoxylated, andmixtures of ethoxylated and propoxylated ethers of fatty alcohols withfrom about 12-26 carbon atoms; and mixtures thereof.

Suitable non-volatile organic ester oils that can also be useful in thecompositions are preferably selected from one or more of the following:triglyceride esters such as vegetable and animal fats and oils;acetoglyceride esters such as acetylated monoglycerides; ethoxylatedglycerides such as ethoxylated glyceryl monostearate; alkyl and alkenylesters of fatty acids having 10 to 20 carbon atoms; ether-esters such asfatty acid esters of ethoxylated fatty alcohols; polyhydric alcoholesters such as ethylene glycol mono and di-fatty acid esters, diethyleneglycol mono-and di-fatty acid esters, polyethylene glycol (200-6000)mono- and di-fatty acid esters, propylene glycol mono- and di-fatty acidesters, polypropylene glycol 2000 monooleate, polypropylene glycol 2000monostearate, ethoxylated propylene glycol monostearate, glyceryl mono-and di-fatty acid esters, polyglycerol polyfatty esters, ethoxylatedglyceryl monostearate, 1,2-butylene glycol monostearate, 1,2-butyleneglycol distearate, polyoxyethylene polyol fatty acid ester, sorbitanfatty acid esters, and polyoxyethylene sorbitan fatty acid esters; andliquid C1-C30 mono- and poly-esters of sugars and related materials suchas glucose tetraoleate, the glucose tetraesters of soybean oil fattyacids (unsaturated), the mannose tetraesters of mixed soybean oil fattyacids, the galactose tetraesters of oleic acid, the arabinosetetraesters of linoleic acid, xylose tetralinoleate, galactosepentaoleate, sorbitol tetraoleate, the sorbitol hexaesters ofunsaturated soybean oil fatty acids, xylitol pentaoleate, sucrosetetraoleate, sucrose pentaoletate, sucrose hexaoleate, sucrosehepatoleate, sucrose octaoleate, and mixtures thereof.

Other more preferred non-volatile organic oils are propoxylated ethersof C14-C18 fatty alcohols, esters of C2-C8 alcohols and C12-C26carboxylic acids (e.g. ethyl myristate, isopropyl palmitate), esters ofC12-C26 alcohols and benzoic acid (e.g. Finsolv TN supplied by Finetex),diesters of C2-C8 alcohols and adipic, sebacic, and phthalic acids(e.g., diisopropyl sebacate, diisopropyl adipate, di-n-butyl phthalate),polyhydric alcohol esters of C6-C26 carboxylic acids (e.g., propyleneglycol dicaprate/dicaprylate, propylene glycol isostearate); andmixtures thereof. Most preferred are esters of C12-C15 alcohols andbenzoic acids (Finsolv TN).

Other more preferably non-volatile organic oils include octylhydroxystearate, cetyl palmitate, octyl hydroxystearate, cetylpalmitate, octyl palmitate (Wickenol 155) and the like; and ethyl,isopropyl, and butyl esters of fatty acids having 10 to 20 carbon atomssuch as hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropylpalmitate, decyl oleate, isodecyl oleate, hexadecyl stearate, decylstearate, isopropyl isostearate, diisopropyl adipate, diisohexyladipate, dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate,myristyl lactate, and cetyl lactate.

Preferred emulsifiers or surfactants used for preparing the oil-in-wateremulsion can be nonionic, anionic or cationic. Illustrative nonionicsurfactants are alkoxylated compounds based on C10-C22 fatty alcoholsand acids, and sorbitan. These materials are available, for instance,from the Shell Chemical Company under the Neodol trademark, Copolymersof polyoxypropylene-polyoxyethylene, sold by the BASF Corporation underthe Pluronic trademark, can also useful as can alkyl polyglycosidesavailable from the Henkel Corporation. Anionic type emulsifiers orsurfactants include fatty acid soaps, sodium lauryl sulphate, sodiumlauryl ether sulphate, alkyl benzene sulphonate, mono- and di-alkyl acidphosphates and sodium fatty acyl isethionate. Amphoteric emulsifiers orsurfactants include such materials as dialkylamine oxide and varioustypes of betaines (such as cocamidopiopyl betaine). The overallconcentration of the emulsifier can be from 0% to about 10% of theformulation, preferably from 0.1% to about 5% and most preferably fromabout 0.1% to about 2%, by weight of the composition.

Examples of preferred nonionic surfactants are polyoxyethylene fattyacid partial ester, polyoxyethylene sorbitan fatty acid partial ester,polyoxyethylene glycerol fatty acid partial ester, polyglycerol fattyacid partial ester, fatty acid alkanol amide, fatty acid alkanolamide-ethylene oxide addition product, polyoxyethylene glycerol fattyacid, monoglycerol pyroglutamate, and glycerol acylglutamate. Otherexamples of useful non-ionic surfactant include polyethylene glycolether of stearyl alcohol of the formula CH3 (CH2)16 CH2 (OCH2 CH2)n OH,wherein n is 21; a polyethylene glycol ether of stearyl alcohol of theformula: CH3 (CH2)16 CH2 (OCH2 CH2)n OH, wherein n is 2 (availablecommercially as Brij 721 and Brij 72 from ICI Americas); Peregal fattyalcohol polyoxyethylene (Peregal A-20) ether having a formulaRO(CH2CH2O)-20H (a polyoxyethylene alkyl ethers), or mixture thereof.

Examples of preferred anionic surfactants are alkyl sulfate,polyoxyethylene alkyl sulfate, fatty acid amide ether sulfate,alkylbenzene sulfonate, alkyloxy sulfonate, sulfosuccinic acid higheralcohol ester salts, N-long-chain fatty acid acyl-N-methyl-taurinesalts, fatty acid salts, N-long-chain acyl glutamate, N-long-chain acylsarcosine salts, and monoalkyl phosphate.

The oil phase of the oil-in-water emulsions can also comprise anoil-soluble antioxidant. Preferred oil-soluble antioxidants useful inthe compositions of the present invention include butylatedhydroxytoluene (BHT), ascorbyl palmitate, butylated hydroxyanisole(BHA), phenyl-a-naphthylamine, hydroquinone, propyl gallate,nordihydroguaiaretic acid, rosemary extract and mixtures thereof.

The oil phase may also comprise retinoid compounds. Suitable retinoidcompounds include Vitamin A alcohol (retinol), Vitamin A aldehyde(retinal) and Vitamin A esters (retinyl acetate and retinyl palmitate),although other retinoids may be incorporated into the emulsioncompositions of this invention.

The oil-in-water emulsions can be prepared as cream or lotionformulations, as desired, by varying the relative quantities of the oiland water phases of the emulsion. The pH of the compositions arepreferably in the range of from about 2 to about 6 since it appears thatpsoralens, particularly 8-MOP, tend to be more unstable in basicsolution. Buffering agents can be used to maintain an established pH ofthe composition. Examples of buffering agents include calcium acetate,potassium metaphosphate, potassium phosphate monobasic, sodium citrate,and tartaric acid.

The oil-in-water formulations of the present invention are preferablyprepared accoording well known mixing and blending procedures. Forexample, for emulsion products of the present invention, each phase ofthe emulsion is separately prepared with all of the components containedin their appropriate phases. The emulsion is formed by combining onephase to the other with agitation.

In an exemplary process for preparing such a formulation, water phaseingredients are weighed and combined slowly with agitation. Where athickener is used such as Carbopol 934, it is preferably the lastingredient added and it too is combined slowly with agitation. The waterphase is heated to about 80 C. The oil phase ingredients are weighed,combined, and heated to 80 C. as well. The oil phase is then added tothe water phase with agitation. The combined materials are then cooledat 45 C. QS with water and homogenized for 1 minute before cooling toroom temperature.

The most preferred oil-in-water emulsion is an 8-MOP Lotion with (Octylmethoxycinnamate) as the UVB absorber. The most preferred formulation isas follows:

% Water Phase Water (carrier) 58.2 Sorbitol (preservative) 3 Methylparaben (preservative) 0.2 Carbopol 934 (thickener) 0.3 Oil Phase Brij721(emulsifier) 1 Finsolv TN (solvent/emollient) 12.4 Octylmethoxycinnamate 7.5 (UVB absorbing agent) Wickenol 15 (emollient) 15propyl paraben (preservative) 0.3 Sodium Stearate C-1 2(thickener/barrier) Methoxsalen (8-MOP) 0.1 100%

Another preferred lotion has the following formulation:

Function % Water Phase Carrier Water 58.2 Preservative Sorbitol 3Preservative Methyl paraben 0.2 Thickener Carbopol 934 0.3% 0.3 OilPhase Emulsifier Brij 721 1.0 Solvent/Emollient Finsolv TN 12.4 UVBabsorber Octyl methoxycinnamate 7.5 Emollient Wickenol 155 15Preservative propyl paraben 0.3 Thickener/barrier Sodium Stearate C-1 2Psoralen Methoxsalen (8-MOP) 0.1 100%

In each case, for the oil phase methoxsalen is weighed out and added tothe mixture of Finsolv TN and octyl methoxycinnamate. It is then heatedto temperature with constant stirring until the methoxsalen iscompletely dissolved and held at that temperature for 5 minutes. Theremainder of the oil phase components are then combined with it at thephasing temperature and cooled as described above.

A placebo oil-in-water emulsion useful in comparative testing of thecompositions of the invention has the following formulation:

Function % Water Phase Carrier Water 58.2 Preservative Sorbitol 3Preservative Methyl paraben 0.2 Thickener Carbopol 934 (or equivalent)0.3 Oil Phase Emulsifier Brij 721 1.0 Solvent/Emollient Finsolv TN 12.5UVB absorber Octyl methoxycinnamate 7.5 Emollient Wickenol 155 15Preservative propyl paraben 0.3 Thickener/barrier Sodium Stearate C-1 2100%

An oleaginous formulation of photoactive agent and an agent that blocksor absorbs extraneous radiation can also be prepared from the emollientoils and substantive oils or wax as described above. Water (except foradventitious trace of water which may be present in the oil phase) isnot a component of such a formulation. Preferably, the activeingredients include a psoralen such as 8-MOP and a UVB absorbing agent.Optionally, this oleaginous formulation may further comprise antioxidantsuch BHT, lower alkyl alcohols such as ethanol or propanol, or butanol,including mixtures thereof; animal and vegetable oils such as beeswax,Japan wax, whale wax, carnauba wax, candelilla wax, cacao oil, cetylalcohol, stearyl alcohol, oleic acid, stearic acid, lanoline, olive oil,tsubaki oil, avocado oil, coconut oil, jojoba oil, cottonseed oil,castor oil, peanut oil, wheatgerm oil, oleyl alcohol, squalane;vaseline; oils and fats such as isopropyl myristate, isopropylpalmitate, oleyl oleate, isostearic acid, and octyl dodecanol.

The most preferred oleaginous lotion of this invention is an 8-MOP andUVB lotion having the following formulation:

Wheatgerm oil 1.0 g Isopropyl Myristate 24.9 g  Butyl-hydroxy-toluene0.1 g Peanut oil q.s.p. 100.0 g  8-MOP 0.1%   2-ethylhexylp-aminodimethylbenzoate 2% ethyl alcohol (ethanol) 5%When prepared as an oleginous ointment, the following formulation ispreferred:

8-MOP 0.1% (0.1 g) 2-ethylhexyl p-aminodimethylbenzoate 2% Sodium Laurylsulfate 1.00 g Propylene glycol 6.00 g Stearylic alcohol 10.00 g Vaseline 56.00 g  Methyl parahydroxybenzoate 0.05 g

The methods of the invention are used to alleviate at least one symptomof psoriasis, vitiligo, cutaneous T-cell lymphoma, sleroma, chroniclymphocytic leukemia, atopic dermatitis, or adult T-cell leukemia. Themethod of the present invention allows for both 1) protection of an areasurrounding the affected area of a patient and 2) protection of theaffected area from harmful extraneous (preferably UVB) irradiation. Themethod comprises a) contacting a therapeutical pharmaceuticalcomposition according to the invention to an affected area; b)contacting an area surrounding the affected area with an agent thatblocks or absorbs extraneous radiation agent; and c) irradiating theaffected area with UVA light.

Preferable agents for blocking or absorbing extraneous radiation thatare applied to areas surrounding the affected area are UVA and/or UVBabsorbing agents.

Preferred UVA absorbing agents that can be used with step b) includedibenzoylmethane derivatives, anthranilate derivatives such asmethylanthranilate and homomethyl, 1-N-acetylanthranilate, and mixturesthereof. Examples of dibenzoylmethane agents are described in U.S. Pat.No. 4,387,089 issued to Depolo. More preferred UVA absorbing agents aredibenzoylmethane agents and their derivatives, including but not limitedto, those selected from 2-methyldibenzoylmethane,4-methyldibenzoylmethane, 4-isopropyldibenzoylmethane,4-tert-butyldibenzoylmethane, 2,4-dimethyldibenzoylmethane,2,5-dimethyldibenzoylmethane, 4,4′-diisopropylbenzoylmethane,4-(1,1-dimethylethyl)-4′-methoxydibenzoylmethane,2-methyl-5-isopropyl-4′-methoxydibenzoylmethane,2-methyl-5-tert-butyl-4′-methoxy-dibenzoylmethane,2,4-dimethyl-4′-methoxydibenzoylmethane,2,6-dimethyl-4′-tert-butyl-4′methoxydibenzoylmethane, and mixturesthereof. Preferred dibenzoyl agents include those selected from4-(1,1-dimethylethyl)-4′-methoxydibenzoylmethane,4-isopropyldibenzoylmethane, and mixtures thereof. A more preferred UVAabsorbing agent is 4-(1,1-dimethylethyl)-4′-methoxydibenzoylmethane.

The UVA absorbing agent4-(1,1-dimethylethyl)-4′-methoxydibenzoylmethane, which is also known asbutyl methoxydibenzoylmethane or Avobenzone, is commercially availableunder the names of Parsol™ 1789 from Givaudan Roure (International) S.A. (Basel, Switzerland) and Eusolex™ 9020 from Merck & Co., Inc(Whitehouse Station, N.J.). The UVA absorbing agent4-isoproplydibenzoylmethane, also known as isopropyldibenzoylmethane, iscommercially available from Merck under the name of Eusolex™ 8020.

The method of the present invention may further comprise contacting theaffected area with topical steroids, topical anthralin cream (1%) orhigh dose/short duration anthralin in 1% salicylic acid in petroleum, orthe topical synthetic retinoid tazarotene, retinoids, calcipotriene, ora vitamin D analogue (vitamin D3 or calcipotriol).

An efficacy assessment is preferably performed prior to beginningtreatment, during the treatment, or after one or more elements of thetreatment have been administered. For example, for psoriasis a subjectis evaluated for the FDA-recommended efficacy endpoint for psoriasismedications and/or treatments. Examples of such endpoints include PASI75 reduction or a physician global assessment. Objective methodsemployed for establishing the effect of treatment of psoriasis patientsinclude the resolution of plaques by visual monitoring and withphotography. The visual scoring is done using PASI (Psoriasis Area andSeverity Index) score (see Fredericksson, A J, Peterssonn B CDermatologies 157:238-244 (1978)). Topical administration is bestaccomplished when the composition of the invention is in the form ofsolutions, ointments, or creams.

Administration is best accomplished when only an effective amount of theactive ingredient per unit area is involved. Illustratively a onepercent solution, suspension, or ointment is applied on the order ofone-tenth milliliter per square centimeter, in association with asuitable carrier, e.g., ethanol, or other carrier of types alreadymentioned. Following administration of the compound, the patient isirradiated with UVA at a dose ranging from 0.2 to 15 joules/cm². Theamount and duration of irradiation will depend upon a number of factorsincluding the type and the extent of the disease being treated, the ageof the patient and other dosing factors known in the art.

In conventional phototherapies including prior PUVA methods, UVB andnarrow band UVB, the initial dose (J/cm2) of light to be used isdetermined by the patient's skin type classification. (Type 1-6) Theinitial dose of light is started at a very low dose (enough to provide aslight light pink color to the normal skin) The dose of light energy issystematically increased during subsequent therapies. For example inexisting PUVA therapy a treatment regimen would be as follows:

Initial dose Increase in lightInitial dose of light (J/cm2) dose every 3days (J/cm2) Type 1 skin 1 0.5 Type 2 skin 2 1.0 Type 3 skin 3 1.0 Type4 skin 4 1.0 Type 5 skin 5 1.5 Type 6 skin 6 1.5See, Zanoli M, Feldman S, Clark A and Fleischer A, Phototherapytreatment protocols for psoriasis and other phototherapy responsivedermatoses 2000. Standard treatment rules are applied to decrease thedosage should the skin be red after any therapies or if a dose ismissed. Because psoriasis plaques are more resistant to sun burning dueto the amount of energy they adsorb the dose of light for the preferredmethod of the invention incorporates a low dose regimen that can startwith a higher dose of light during initial therapies because the normalhealthy skin will not be exposed to the drug or light. Therefore skinburning of healthy skin is not a concern. Higher dosages of light in theinitial therapies will be followed by a decrease in light energy as thepsoriasis plaque lesions heals and returns to normal skin quality. Thisprocess is an inverse of what is performed using the priorphototherapies because of the elimination of systemic exposure to normalskin. The use of higher doses of UVA light dosage in the presence oftopical psoralen provides a faster response (normalization of skin) andthe patient will enter a short maintenance phase at lower dose of lightto prevent the normalized skin (healed psoriasis plaque) to prevent anyburning of the new skin. It is also possible to use the compositions ofthe invention following the low dose to high treatment regimen.

EXAMPLES Example 1 Preparation of Compositions

Two oil-in-water formulations containing methoxsalen(8-methoxypsoralen—UV photosensitizer) and octylmethoxycinnamate (UVBsunscreen) were prepared. One formulation contained 0.09% methoxsalen,the second contained 0.01% methoxsalen. Both creams contained 7.5%octymethoxycinnamate.

The compositions were prepared as follows:

Water Phase

-   1. Tare main container. To this, add DI water.-   2. Add Carbopol 934 slowly with propeller agitation, mix until    uniform.-   3. Add rest of water phase ingredients, and heat to 80 C., mix until    uniform.-   4. Hold at 80 C. for phasing    Oil Phase-   1. Into another beaker add oil phase ingredients and heat to 80 C.,    with propeller mixing.-   2. Mix until uniform, and hold for phasing.    Phasing-   1. When both phases are at 80 C. and uniform, add oil phase into    water phase.-   2. Continue to mix until uniform.-   3. When batch is uniform, cool to 45 C. and QS with water.-   4. Homogenize for 1 minute at 30 psi.-   5. Fill into appropriate container.    Formulation 1:

I. CTFA Name II. Trade Name Function Wt. % Required Water PhaseDeionized Water Water Solvent 58.20 1164.00 Sorbitol 70% Sorbitol 70%humectant 3.00 60.00 Carbopol 934 Carbomer thickner 0.30 6.00Methylparaben Methylparaben preservative 0.20 4.00 Oil Phase C12-15Alkyl Benzoate Finsolv TN Solubilizing agent 12.40 248.00 OctylMethoxycinnamate Parsol MCX Sunsceen Active 7.50 150.00 Octyl PalmitateWickenol 155 emolient 15.00 300.00 Propylparaben Propylparabenpreservative 0.30 6.00 Steareth 21 Brij 721 emulsifier 1.00 20.00 SodiumStearate C-1 Sodium Stearate C-1 emulsifier 2.00 40.00 Methoxsalenactive 0.10 2.00 total: 100.00 2000.00Formulation 2:

CTFA Name Trade Name Function Wt. % Required Water Phase Deionized WaterWater Solvent 58.29 1165.80 Sorbitol 70% Sorbitol 70% humectant 3.0060.00 Carbopol 934 Carbomer thickner 0.30 6.00 MethylparabenMethylparaben preservative 0.20 4.00 Oil Phase C12-15 Alkyl BenzoateFinsolv TN Solubilizing agent 12.40 248.00 Octyl Methoxycinnamate ParsolMCX Sunsceen Active 7.50 150.00 Octyl Palmitate Wickenol 155 emolient15.00 300.00 Propylparaben Propylparaben preservative 0.30 6.00 Steareth21 Brij 721 emulsifier 1.00 20.00 Sodium Stearate C-1 Sodium StearateC-1 emulsifier 2.00 40.00 Methoxsalen active 0.01 0.20 total: 100.002000.00A placebo formulation was also prepared as follows:

CTFA Name Trade Name Function Wt. % Required Water Phase Deionized WaterWater Solvent 58.20 1164.00 Sorbitol 70% Sorbitol 70% humectant 3.0060.00 Carbopol 934 Carbomer thickner 0.30 6.00 MethylparabenMethylparaben preservative 0.20 4.00 Oil Phase C12-15 Alkyl BenzoateFinsolv TN Solubilizing agent 12.50 250.00 Octyl Methoxycinnamate ParsolMCX Sunsceen Active 7.50 150.00 Octyl Palmitate Wickenol 155 emolient15.00 300.00 Propylparaben Propylparaben preservative 0.30 6.00 Steareth21 Brij 721 emulsifier 1.00 20.00 Sodium Stearate C-1 Sodium StearateC-1 emulsifier 2.00 40.00 total: 100.00 2000.00

Example 2 Skin Photosensitization

Both formulations were tested for ability to photosensitive human skinwhen applied topically followed by UVA exposure. The creams were appliedto the skin of a healthy male, human volunteer and to which UVA was thenapplied.

The UVA exposure source was a 100 W xenon arc solar simulator filteredwith WG345 Schott filter. Without a photosensitizer, the UVA doserequired for an erythema reaction is approximately 40 J/cm². Thisfiltration system eliminates virtually all radiation from the source(radiation below 340 nm). This is unlike the fluorescent UVA lamps usedfor PUVA therapy which contain both UVA2 and UVA1, as well as 2% UVBradiation. Comparisons of the efficacy of these two sources using an8-MOP action spectrum (Cripps BJID 107:77-82. 1982) shows that thefluorescent PUVA bulbs are 2.25× more effective than the solar simulatorsource used in the following experiments. Therefore, estimatedequivalent exposures for PUVA phototherapy lamps are 2.25× lower thanthe exposure doses given below for the UVA filtered xenon solarsimulator. Soak time refers to the time that the topical composition wasallowed to stand on the subject's skin prior to UVA exposure.

Minimal “Soak” Phototoxic Dose time UVA exposures (observation Day)Formulation 2 15 mins 0.5, 0.7, 0.9, 1.3, 1.8 J/cm² None observedFormulation 1 15 mins 0.7, 0.9, 1.3, 1.8, 2.5 J/cm² None observed

No erythema responses were observed over a three day period. It wasconcluded that the exposure doses used are insufficient to elicit aphototoxic erythema reaction. No erythema reaction is seen with theplacebo formulation.

Higher doses of UVA exposure were then applied to determine whether theywould elicit a phototoxic skin reaction. Formulation 2 was used:

UVA “Soak” time exposures Responses Formulation 2 15 mins 2.5, 4, 5,Mild erythema responses 6.3, 8.0 J/cm² 6.3, and 8 J/cm² 1 day afterexposure - 6 days (ongoing)

Phototoxic reactions occurred with UVA doses of 6-8 J/cm² after only 15minutes exposure time of the topical on the skin. The subject would havebeen protected from extraneous radiation in the form of UVB radiationhad it been emitted.

Longer soak times between formulation application and exposure was thentested and MPD (Minimal Phototoxic Dose) UVA was determined. Bothconcentrations of methoxsoralen cream were applied and allowed to dryand soak into the skin for 30 minutes before the start of UVA exposureswith the Solar Simulator (UVA only).

“Soak” UVA Minimal Phototoxic time exposures Dose (observation Day)Formulation 2 30 mins 2.5, 4, 5, Progressive erythema 6.3, 8 J/cm²responses starting with lowest dose observed 2 days after UVA exposure.Highest doses with deep erythema response 5 visible 5 days afterexposure Formulation 1 30 mins 4.0, 5, 6.3, Mild erythema on the two 8,10 J/cm² highest doses observed 2 days pose exposure, still visible 5days later

Photosensitization to UVA radiation was achieved within exposure timesat or below 30 minutes and well below the exposure time needed for askin erythema reaction without the presence of the photosensitizing8-MOP cream (40 J/cm²). The subject would have been protected fromextraneous radiation in the form of UVB radiation had it been emitted.

Example 3 Dose Response Study

A dose response study of UVA exposures with topical creams containing0.1% wt (high dose) and 0.01% wt. (low dose) 8-MOP was conducted todetermine UV dose requirements in a Yucatan mini-pig. This minimumresponse (tanning) dose was delivered on 5 occasions over a two-weekperiod. Increased pigmentation and the duration of this pigmentationwere evaluated over the subsequent three-month time period. UVBexposures (without the cream) were also evaluated.

Subjects were treated 2-3 times per week for a total of 6 treatmentswith UVA doses of 15 minutes or 30 minutes. Pigmentation induction wasmonitored with Chromameter Photographs. Pigmentation regression was alsomonitored in this manner. UVA (approx. 350 nm with a minor peak atapprox. 320 nm) was generated from a.lamp bank of 8, 40 W F40350lightbulbs. Total UVA irradiance at the exposure plane was approximately18 mW/cm² For UVB, a Schott WG320 1 mm filter was interposed between thelamps and the spectroradiometer entrance to filter short wavelength UVBfrom the source to more closely replicate the effective spectrum of anarrow band UVB source used in phototherapy for psoriasis. Filteredirradiance at the exposure plane was 8 mW/cm². Skin darkness wasmeasured as Delta L using a calibrated Minolta CR300 Chromameter.

Evaluation of skin darkening and regression showed that UVA dosesignificantly effects response. A high psoralen dose with low UVA doseyielded a lower pigment than did the low psoralen and high UVA dose.Peak pigment darkening was observed at day 14, 5 days after the lasttreatment. 0.01% psoralen with 30 min soak and 10 J showed equivalentdarkening to placebo. 0.01% psoralen with 15 min soak and 15.6 J alsoshowed equivalent darkening to placebo. Unfiltered UVB significantlydarkened skin pigment. The Yucatan mini-pig used in this study appearedto behave similarly to human skin type IV-V.

Example 4 Soak Time Study

The experiments described in Example 4 were essentially repeated exceptthat 10, 20, and 30 minute soak times were evaluated for 0.01% wt and0.1% wt psoralen compositions.

Again, unfiltered UVB provided the most potent pigment darkening effectwhich was greatly reduced upon filtration. Pigment induction was verysimilar for the 0.1% wt psoralen composition whether the soak time was10, 20, or 30 minutes—all were equally efficacious. The 0.01% wtsolution did not produce pigmentation significantly greater than placebowhether soak time was 10, 20, or 30 minutes.

Example 5 Psoralen Cream Study

A non-pigmented Gottingen pig was studied for the effects of UVA doseusing a 0.1% wt psoralen cream. Two different light sources were used: abroad spectrum UVA lamp (traditionally used for PUVA therapy) and anarrow spectrum lamp. UVB was also evaluated.

Hair was removed from the subject around the area to be tested. Thetopical cream was applied at 4 mg/cm² over an area 50 cm². Theapplication was given a 30 minute soak time. Broad and narrow band dosesof UVA were applied at 0.5, 1, 2, 3, 4, and 5 J/cm² doses. Monitoringfor erythema occurred for up to 144 hours.

For the broad band UVA, an erythema was observed for all UVA dosesgreater than 1 J/cm². Maximum responses occurred from 72-96 hours afterexposure.

For the narrow band UVA (365 nm), an erythema response was induced at1-2 J/cm² and greater. Responses appeared more intense than those of thebroad band UVA source. Responses appeared to be more “all-or-none”rather than a gradual increase over the range of UVA intensities.

The formulations of materials used in Examples 3-5 is shown below:

0.01% Cream III. CTFA Name IV. Trade Name Wt. % Water Phase DeionizedWater Water 58.30 Sorbitol Sorbitol 3.00 Carbopol Ultrez 10 0.30Methylparaben Methylparaben 0.20 Oil Phase C12-15 Alkyl Benzoate FinsolvTN 12.49 Octyl Methoxycinnamate Parsol MCX 7.50 Octyl Palmitate Wickenol155 15.00 Propylparaben Propylparaben 0.20 Steareth 21 Brij 721 1.00Sodium Stearate C-1 Sodium Stearate C-1 2.00 Methoxsalen 0.1 100.00

0.1% Cream: CTFA Name Trade Name Wt. % Water Phase Deionized Water Water58.3 Sorbitol 70% Sorbitol 70% 3.00 Carbopol Ultrez 10 0.30Methylparaben Methylparaben 0.20 Oil Phase C12-15 Alkyl Benzoate FinsolvTN 12.40 Octyl Methoxycinnamate Parsol MCX 7.50 Octyl Palmitate Wickenol155 15.00 Propylparaben Propylparaben 0.20 Steareth 21 Brij 721 1.00Sodium Stearate C-1 Sodium Stearate C-1 2.00 Methoxsalen 0.1 100.00A placebo formulation was also prepared as follows:

CTFA Name Trade Name Wt. % Water Phase Deionized Water Water 58.30Sorbitol Sorbitol 3.00 Carbopol Ultrez 10 0.30 MethylparabenMethylparaben 0.20 Oil Phase C12-15 Alkyl Benzoate Finsolv TN 12.50Octyl Methoxycinnamate Parsol MCX 7.50 Octyl Palmitate Wickenol 15515.00 Propylparaben Propylparaben 0.30 Steareth 21 Brij 721 1.00 SodiumStearate C-1 Sodium Stearate C-1 2.00 100.00UVA/UVB Blocker (all percents are wt %):

Water Phase: Purified Water 67.3% Carbopol Ultrez 10 0.40% Glycerin 9173.00% Sodium Hydroxide 0.40% Lipid Phase Mecheliopan OS 5.00% Parsol1789 3.00% Necheliopan BB 3.00% Parsol MCX 2.00% Amphisol K 3.00% CetylAlcohol 0.60% Stearyl Alcohol 0.60% Cetiol LC 2.50% Dow Corning 580 Wax.  84% Bisobolol 0.10% BHT 0.02% Dow 200 Fluid 50 1.25% Hallbrite TQ5.00% Post Additions Versene 100XL 0.66% Phenonip 1.00% Citric AcidAnhyd. <.10%

1. A composition for use in phototherapy comprising a photoactivablecompound and an agent that absorbs or blocks extraneous radiationwherein the compound is 8-methoxy-psoralen, the agent isoctylmethoxycinnamate, and wherein the composition together withpharmaceutically acceptable carriers is prepared in the form of a gel,lotion or ointment.
 2. A composition of claim 1, wherein said psoralenconcentration is about 0.01-10% by weight of said composition.
 3. Acomposition of claim 2, wherein said psoralen concentration is about0.01-5% by weight of said composition.
 4. A composition of claim 3,wherein said psoralen concentration is about 0.05-1% by weight of saidcomposition.
 5. A composition of claim 1, wherein said agent thatabsorbs or blocks extraneous radiation is about 1-10% by weight of saidcomposition.
 6. A composition of claim 5, wherein said photactivatableagent is a psoralen at a concentration of about 0.1-1% by weight of saidcomposition; and said agent that absorbs or blocks extraneous radiationis a UVB absorbing agent at a concentration of about 1-10% by weight ofsaid composition.
 7. A pharmaceutical oil-in-water emulsion compositioncomprising: from about 0.05% to 0.4% of a psoralen; from about 4% to 15%of an agent that absorbs or blocks extraneous radiation; from aboveabout 0 to about 80% of water; from about 10% to 40% of a non-volatileorganic oil; from about 1 to 5% of a thickener; and from about 0.5% to2% of an emulsifer. wherein the psoralen is 8-methoxy-psoralen, theagent is octylmethoxycinnamate, and wherein the composition comprisesoctyl palmitate and propyl paraben.
 8. A composition of claim 7 propylparaben comprises from about 0.1% to 5% of the emulsion.
 9. Apharmaceutical oil-in-water emulsion composition comprising: 58% water,3% sorbitol; 3.0%, 0.2% methyl paraben , 0.3% propyl paraben, 0.3%Carbopol 934, 1% Brij 721, 12.4% Finsolv TN, 7.5% octylmethoxycinnamate, 15% Wickenol 155, 2.0% sodium Stearate C-1, and 0.1%8-methoxypsoralen (8-MOP).
 10. A composition of claim 9 furthercomprising an antioxidant.